1. Field of the Invention
This invention relates to a process for producing 1-betamethyl carbapenem antibiotic intermediates involving isomerizing an alphamethylated azetidinone alkyl carboxylic ester under basic conditions.
2. Brief Description of Disclosures in the Art
Since the discovery of thienamycin, ##STR1## an extremely potent broad spectrum antibiotic, disclosed and claimed in commonly assigned U.S. Pat. No. 3,950,357, a large amount of research activity has been conducted in the medicinal chemistry area for other active analogs not having its associated deficiencies, i.e. chemical instability at high concentration and susceptibility to renal dipeptidase.
In addition to the N-formimidoyl derivative of thienamycin, disclosed and claimed in commonly assigned U.S. Pat. No. 4,194,047, among some of the more promising analogs that have been developed are the 1-betamethyl compounds of the structure, i.e., ##STR2## in which the 1-methyl group is in the beta configuration and R is a radical known in the antibiotic art.
Synthesis of the above 1-beta methyl analogs is desired in large quantities for derivatization and pharmacological evaluation and requires a process which is environmentally safe for the introduction of the beta-methyl substituent in a manner designed to yield a high percentage of the beta-methyl intermediate prior to ring closure.
A published procedure by Shih et al. in Heterocycles, Vol. 21, No. 1, pp. 29-40 (1984) describes a process for alkylating the 4-alkyl side chain of certain azetidin-2-ones in the presence of hexamethylphosphoramide (HMPA) as a cosolvent, to produce a mixture of the alpha-and beta-methyl isomers in about a 4:1 molar ratio. Also described is an epimerization process employing HMPA resulting in a 1:1 beta/alpha methyl isomer ratio.
Desirably, a pilot plant or commercial synthesis should achieve higher beta/alpha isomeric molar ratios than this and the use of hexamethylphosphoramide should be avoided due to its known carcinogenicity.
It is therefore an object of this invention to provide a process for producing intermediates useful in making 1-betamethylcarbapenem antibiotics. It is further an object of this invention to provide a process for producing intermediates in high yield having the necessary 1-beta methyl stereochemistry, prior to ring closure to the carbapenem ring system, in which the products contain the beta methyl/alpha methyl isomers in a molar ratio greater than one. These and further objects of the invention will become obvious from the accompanying disclosure as set forth herein.